Browsing by Author "Janse Van Rensburg, Mari"
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- ItemSynthetic routes towards triazole cannabidiol analogues and substituted cycloparaphenylenes(Stellenbosch : Stellenbosch University, 2019-12) Janse Van Rensburg, Mari; Van Otterlo, Willem A. L.; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Cancer is the leading cause of death worldwide and current treatment options often lead to painful and unpleasant side-effects. The active constituents isolated from medicinal plants have been successfully developed into various chemotherapeutic agents. The medicinal plant of interest in this research project, the cannabis plant, along with the constituents isolated, known as cannabinoids, have shown promising proapoptotic, anti-proliferative and anti-angiogenic effects. Interest in non-psychoactive cannabinoids, in particular cannabidiol (CBD), has significantly increased in recent years. CBD offers the hope of improved anticancer therapies that selectively target cancer cells without affecting normal cells, thereby eliminating the unwanted side-effects associated with conventional therapies. This project involved the design and synthesis of CBD analogues by mimicking the main pharmacophoric groups found on the structure of CBD. The main difference between the natural occurring cannabinoid and the analogues in this study, was the replacement of the benzene ring at the core of the structure with a 1,2,3-triazole ring using click chemistry. A triazole moiety can provide improved solubility and bioavailability, while helping to exploit the chemical space around the compound. Three different systems (Scaffold A, B and C) were explored throughout this project. The transitions between these systems involved systematic alterations of functional groups on the general structure of each system, as well as the introduction of stereochemistry in the synthesis of Scaffold C. Important reactions used during the synthesis of these scaffolds included an epoxide ring opening via nucleophilic substitution, a Michael reaction, an Appel reaction, a nucleophilic substitution reaction resulting in an inversion of stereochemistry, as well as copper- and ruthenium-catalyzed azide alkyne cycloaddition reactions. These reactions provided the 1,4- and 1,5-, as well as 1,4,5-polysubstituted 1,2,3-triazole CBD analogues. The anticancer activity of these compounds was subsequently evaluated against the MCF-7 cell line, as well as the HeLa cell line. None of the CBD triazole analogues of this study showed particularly appealing activity against these cancer cell lines. One analogue did however show potentially interesting activity against the MCF-7 cell line, and two analogues had an IC50 value below 100 μM against the HeLa cell line, with the most promising analogue providing an IC50 value of 74.3 μM. In addition, all compounds tested were completely devoid of toxicity below concentrations of 100 μM. The results obtained provide valuable insight into the future design of triazole CBD analogues. The synthesis of complex macrocycles and the study of the structural characteristics and properties displayed by these compounds is a fascinating research field. Cycloparaphenylenes (CPPs) are macrocycles which consist of benzene rings connected through para-linkages. This project focused on the synthesis of functionalized CPPs as these macrocycles could provide new host−guest possibilities, possible use in chemosensors and nanoporous materials and the option of connecting these CPP macrocycles to various surfaces. A method was developed for the synthesis of substituted [8]CPPs containing a thioether functionality, which provides the option of effortlessly transforming the substituents throughout the synthesis to give access to the previously synthesized ether-containing [8]CPP macrocycle. The series of reactions used during the synthesis of this CPP linker system included a Sonogashira coupling reaction, a dibromination reaction and a macrocyclization reaction, among others. A linear test system was developed with a similar backbone structure to the substituted CPPs. The synthesis of the linear test system allowed investigation of the optimum route for the formation of the thioether functionality, which was then directly applied to the CPP linker system to gain access to the sulfur-containing CPP macrocycle.